Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, stimuli induce lytic reactivation that results in disease ranging from recurrent oral or genital lesions to severe ocular disease. The factors which determine the establishment of latency and reactivation are poorly understood although modulation of the chromatin state of the viral genome plays a critical role. The PRC2 histone methyltransferase complex has been implicated in suppression of HSV during latency. However, in 2016-2017, it was determined that inhibition of this complex resulted in suppression of HSV primary infection and reactivation from latency via the enhanced induction of cellular antiviral pathways. These inhibitor compounds were further shown to be broad spectrum antivirals. With respect to the coactivator HCF-1, previous studies have determined that the nuclear transport of HCF-1 in latently infected neurons correlates with viral reactivation and that HCF-1 is rapidly recruited to the promoters of the viral IE genes upon initiation of reactivation. Data also suggests that HCF-1 modulates viral chromatin structure to initiate viral reactivation from latency. In 2016-2017, HCF complexes involved in viral reactivation from latency were isolated and identified.